This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. Primary support for the subproject and the subproject's principal investigator may have been provided by other sources, including other NIH sources. The Total Cost listed for the subproject likely represents the estimated amount of Center infrastructure utilized by the subproject, not direct funding provided by the NCRR grant to the subproject or subproject staff. Influenza A viruses continue to be a public health concern due to the mortality and morbidity associated with seasonal influenza and pandemic influenza. Moreover, the 2009 H1N1 outbreak serves as a reminder of the ability of influenza viruses to generate strains that can cause global pandemics, and that influenza viruses continue to pose a significant threat to public health. Of all the pandemics caused by the influenza viruses in the 20th century, the 1918 pandemic, or "Spanish influenza", was by far the most devastating. One of the intriguing outcomes of the 1918 pandemic is the fact that mortality was highest in young adults and not aged individuals. Two hypotheses can explain this outcome: 1) the dampened adaptive immune response in elderly individuals protected them against destruction by the immune system;2) the presence of cross-neutralizing antibodies directed against other H1N1 viruses protected older individuals. The only way to test these hypotheses is to utilize an animal model where the presence of cross-neutralizing antibodies can be controlled. In these studies we propose to: 1. Define the contribution of viral and host genes to the global host response to infection. 2. Characterize age-related differences in disease progression and host immune response.